There are many memory-related conditions for which therapeutic treatments are under investigation, such as methods to enhance memory or to treat memory dysfunction. For example, memory dysfunction is linked to the aging process, as well as to neurodegenerative diseases such as Alzheimer's disease. Also, memory impairment can follow head trauma or multi-infarct dementia. Many compounds and treatments have been investigated which can enhance cognitive processes, that is, which can improve memory and retention.
For example, the compound D-cycloserine has been discovered recently to provide improvements in cognitive function and to be useful in treatment of cognitive dysfunction, as described in U.S. Pat. application Ser. No. 07/127,121 filed Dec. 1, 1987, now U.S. Pat. No. 4,904,681 and application PCT/US88/04244 filed Dec. 1, 1988.
There are many psychotic states for which therapeutic treatments are under investigation. Drugs which are currently available on the market are thought to act as antagonists at the dopaminergic receptors located in the Central Nervous System (CNS), examples of such drugs being haloperidol and chlorpromazine. These drugs typically induce long lasting and sometimes irreversible side-effects, such as tardive dyskinesia. Thus, the search for improvements in therapy for psychotic disorders has been directed to use of drugs with a different mode of action.
Phencyclidine [1-(-phenylcyclohexyl)piperidine; PCP] is a known general anesthetic and is in use as an animal tranquilizer. PCP is a potent psychotomimetic agent used frequently as a "street" drug. Widespread abuse of PCP has led to increased incidence of PCP-induced psychoses [C. V. Showalter et al, Amer. J Psychiat., 134, 1234 (1977)]. PCP abusers experience an apparent sensory isolation accompanied by a feeling of depersonalization which can be terrifying to the person. These subjective changes make PCP an appropriate drug model for study of schizophrenia. The most impressive evidence that PCP psychosis resembles schizophrenia is the fact that drug users have been mistaken by experienced psychiatrists for schizophrenics before obtaining the history of drug use [S. H. Snyder, Nature, 355-356 (1980)].
PCP has been reported to modulate allosterically the NMDA receptor [P. Loo et al, Eur. J. Pharmacol., 467-468 (1986)] and it has been speculated that the psychotomimetic activity of PCP is related to its antagonism of NMDA transmission [C. A. Tamminga et al, Synapse, 1, 497-504 (1987)]. Facilitation of NMDA transmission by action at the glycine modulatory site may antagonize the effect of an endogenous PCP-like ligand [R. Quirion et al, Peptides, 5, 967-973 (1984)]. Also it has been postulated that glutamatergic action at the glycine-modulated NMDA receptor may be a route to treatment of schizophrenic [S. I. Deutch et al, Clin. Neuropharm., 12, 1, 1-13 (1989)].
D-cycloserine has long been known as a bacteriostatic agent [see The Merck Index, Monograph No. 2747, 10th Edn., Merck & Co., p.395 (1983)]. Its mechanism of action is believed to involve inhibition of cell wall synthesis in susceptible organisms by competing with D-alanine for incorporation into the bacterial cell wall. Also, it is known that the in vitro antibacterial activity of D-cycloserine may be inhibited with D-alanine [Goodman & Gilman, The Pharmacologic Basis of Therapeutics, 7th Edn., MacMillan, N.Y., p. 1209 (1985)].
The compound D-cycloserine, in its D- and L-isomer forms, has also been evaluated for CNS effects in animals [O. Mayer et al, Arzneim. Forsch., 21(2) , 298-303 (1971)]. These cycloserine isomers have also been evaluated for psychological and physiological effects in human subjects. For example, D-cycloserine when administered at 500 mg/day doses to healthy human subjects, appeared to stimulate slight sociability, but with depressed mental alertness [M. Vojtechovsky, Act. Nerv. Super., 7(3) 269 (1965)]. Also, D-cyloserine has been administered at 1000 to 1500 mg/day to healthy volunteers whose blood levels showed increased levels of monoamine oxidase enzyme activity [V. Vitek et al, Psychopharmacologia, 7(3), 203-219 (1965)].
D-cycloserine has been investigated as a therapeutic agent for mental disorders in clinical trials, wherein D-cycloserine was administered to mentally disturbed patients at doses of 500 mg. per day [G. E. Crane, Compr. Psychiat., 2, 51-53 (1961)]. In such clinical trials, improvements in depression, insomnia, anexoria or tension were found for some patients, while patients suffering from severe neurosis or psychosis responded poorly to such medication. Moreover, D-cycloserine has been used to exacerbate the symptoms of schizophrenia in an attempt to cure the ailment by symptom provocation [J. Simeon et al, Compr. Psychiat., 11, 80-88, (1970)]. It appears that D-cycloserine, at the dose levels used in these studies, is acting as an antagonist at the glycine site of the NMDA-PCP receptor complex mimicking the action of PCP by inducing psychosis.
D-cycloserine has been sold commercially for treatment against Mycobacterium tuberculosis. When used at tuberculostatic doses, D-cycloserine is accompanied by many adverse side effects. The most frequent adverse side effects known involve the nervous system. In fact, the limiting factor in use of cycloserine is its CNS toxicity, including both neurologic and psychic disturbances [Drug Evaluation, Chapter 75, American Medical Association, Chicago (1986)]. Patients receiving D-cycloserine have been noted to suffer from drowsiness, dizziness, headache, lethargy, depression, tremor, dysarthria, hyperreflexia, paresthesia, nervousness, anxiety, vertigo, confusion and disorientation with loss of memory, paresis, major and minor clonic seizures, convulsions and coma [G. K. McEvoy et al, American Hospital Formulary Service: Drug Information, 8:16, American Society of Hospital Pharmacists, Bethesda, Md. (1986)].
Other side effects have also been associated with treatments using D-cycloserine. In chronic administration of tuberculostatic doses to patients in clinical trials, D-cycloserine has been observed to produce episodes of diarrhea and oral mucositis. Diarrhea episodes are believed to be linked to depletion of natural intestinal flora by D-cycloserine interference with flora cellular production. Several attempts have been made to reverse this flora depletion effect associated with D-cycloserine treatments. For example, the antibacterial effect of D-cycloserine on Mycobacterium paratuberculosis has been reversed by mycobactin [W. B. Sutton et al, Antibiot. Chemotherapy, 5, 582-584 (1955)]. Patients under treatment with tuberculostatic doses of D-cycloserine, and suffering from diarrhea, have been given preparations of Streptococcus faecium which reduced significantly the episodes of diarrhea [M. Borgia et al, Curr. Therap. Res., 31, 2, 265-271 (1982)]. It is also a well-known remedy to use certain aged, fermented cheeses, such as Camembert or Maroilles cheese, to restore flora depleted by antibiotic treatment.
The growth-inhibiting effect of D-cycloserine on bacteria has been shown to be competitively reversed by D-alanine, a compound noted to be a structural analogue of D-cycloserine [J. W. Moulder et al, J. Bacteriol., 85, 707-711 (1962)]. It has been found that D-cycloserine, as a competitive inhibitor of alanine racemase, is bound to the alanine racemase enzyme 100 times more effectively than the natural substrate D-alanine [U. Roze et al, Mol. Pharmacol., 2, 92-94 (1966)].
Other interactions between D-cycloserine and alanine-type compounds are known. For example, U.S. Pat. No. 4,031,231 describes antibacterial compositions containing 3-fluoro-D-alanine-type compounds, such as 3-fluoro-D-alanine and its deutero analogues, in combination with a 3-fluoro-D-alanine autoantagonist-inhibitor, such as D-cycloserine. These compositions are described as having synergistic antibacterial action.